This invention relates to pyridyl substituted triarylimidazoles which are inhibitors of the transforming growth factor, (xe2x80x9cTGFxe2x80x9d)-xcex2 signaling pathway, in particular, the phosphorylation of smad2 or smad3 by the type I or activin-like kinase (xe2x80x9cALKxe2x80x9d)-5 receptor, methods for their preparation and their use in medicine, specifically in the treatment and prevention of a disease state mediated by this pathway.
TGF-xcex21 is the prototypic member of a family of cytokines including the TGF-xcex2s, activins, inhibins, bone morphogenetic proteins and Mxc3xcllerian-inhibiting substance, that signal through a family of single transmembrane serine/threonine kinase receptors. These receptors can be divided in two classes, the type I or activin like kinase (ALK) receptors and type II receptors. The ALK receptors are distinguished from the type II receptors in that the ALK receptors (a) lack the serine/threonine rich intracellular tail, (b) possess serine/threonine kinase domains that are very homologous between type I receptors, and (c) share a common sequence motif called the GS domain, consisting of a region rich in glycine and serine residues. The GS domain is at the amino terminal end of the intracellular kinase domain and is critical for activation by the type II receptor. Several studies have shown that TGF-xcex2 signaling requires both the ALK and type II receptors. Specifically, the type II receptor phosphorylates the GS domain of the type I receptor for TGF-xcex2, ALK5, in the presence of TGF-xcex2. The ALK5, in turn, phosphorylates the cytoplasmic proteins smad2 and smad3 at two carboxy terminal serines. Generally it is believed that in many species, the type II receptors regulate cell proliferation and the type I receptors regulate matrix production. Therefore, preferred compounds of this invention are selective in that they inhibit the type I receptor and thus matrix production, and not the type I receptor mediated proliferation.
Activation of the TGF-xcex21 axis and expansion of extracellular matrix are early and persistent contributors to the development and progression of chronic renal disease and vascular disease. Border W. A., Noble N. A., N. Engl. J. Med., Nov. 10, 1994; 331(19):1286-92. Further, TGF-xcex21 plays a role in the formation of fibronectin and plasminogen activator inhibitor-1, components of sclerotic deposits, through the action of smad3 phosphorylation by the TGF-xcex21 receptor ALK5. Zhang Y., Feng X. H., Derynck R., Nature, Aug. 27, 1998; 394(6696):909-13; Usui T., Takase M., Kaji Y., Suzuki K., Ishida K., Tsuru T., Miyata K., Kawabata M., Yamashita H., Invest. Ophthalmol. Vis. Sci., October 1998; 39(11): 1981-9.
Progressive fibrosis in the kidney and cardiovascular system is a major cause of suffering and death and an important contributor to the cost of health care. TGF-xcex21 has been implicated in many renal fibrotic disorders. Border W. A., Noble N. A., N. Engl. J. Med., Nov 10, 1994; 331(19):1286-92. TGF-xcex21 is elevated in acute and chronic glomerulonephritis, Yoshioka K., Takemura T., Murakami K., Okada M., Hino S., Miyamoto H., Maki S., Lab. Invest., February 1993; 68(2):154-63, diabetic nephropathy, Yamamoto, T., Nakamura, T., Noble, N. A., Ruoslahti, E., Border, W. A., (1993) PNAS 90:1814-1818, allograft rejection, HIV nephropathy and angiotensin-induced nephropathy, Border W. A., Noble N. A., N. Engl. J. Med., Nov. 10, 1994; 331(19):1286-92. In these diseases the levels of TGF-xcex21 expression coincide with the production of extracellular matrix. Three lines of evidence suggest a causal relationship between TGF-xcex21 and the production of matrix. First, normal glomeruli, mesangial cells and non-renal cells can be induced to produce extracellular-matrix protein and inhibit protease activity by exogenous TGF-xcex21 in vitro. Second, neutralizing anti-bodies against TGF-xcex21 can prevent the accumulation of extracellular matrix in nephritic rats. Third, TGF-xcex21 transgenic mice or in vivo transfection of the TGF-xcex21 gene into normal rat kidneys resulted in the rapid development of glomerulosclerosis. Kopp J. B., Factor V. M., Mozes M., Nagy P., Sanderson N., Bottinger E. P., Klotman P. E., Thorgeirsson S. S., Lab Invest, June 1996; 74(6):991-1003. Thus, inhibition of TGF-xcex21 activity is indicated as a therapeutic intervention in chronic renal disease.
TGF-xcex21 and its receptors are increased in injured blood vessels and are indicated in neointima formation following balloon angioplasty, Saltis J., Agrotis A., Bobik A., Clin Exp Pharmacol Physiol, March 1996; 23(3):193-200. In addition TGF-xcex21 is a potent stimulator of smooth muscle cell (xe2x80x9cSMCxe2x80x9d) migration in vitro and migration of SMC in the arterial wall is a contributing factor in the pathogenesis of atherosclerosis and restenosis. Moreover, in multivariate analysis of the endothelial cell products against total cholesterol, TGF-xcex2 receptor ALK5 correlated with total cholesterol (P less than 0.001) Blann A. D., Wang J. M., Wilson P. B., Kumar S., Atherosclerosis, February 1996; 120(1-2):221-6. Furthermore, SMC derived from human atherosclerotic lesions have an increased ALK5/TGF-xcex2 type II receptor ratio. Because TGF-xcex21 is over-expressed in fibroproliferative vascular lesions, receptor-variant cells would be allowed to grow in a slow, but uncontrolled fashion, while overproducing extracellular matrix components McCaffrey T. A., Consigli S., Du B., Falcone D. J., Sanborn T. A., Spokojny A. M., Bush H. L., Jr., J Clin Invest, December 1995; 96(6):2667-75. TGF-xcex21 was immunolocalized to non-foamy macrophages in atherosclerotic lesions where active matrix synthesis occurs, suggesting that non-foamy macrophages may participate in modulating matrix gene expression in atherosclerotic remodeling via a TGF-xcex2-dependent mechanism. Therefore, inhibiting the action of TGF-xcex21 on ALK5 is also indicated in atherosclerosis and restenosis.
TGF-xcex2 is also implicated in peritoneal adhesions Saed G. M., Zhang W., Chegini N., Holmdahl L., and Diamond M P., Wound Repair Regeneration. 7(6):504-510, 1999 November-December. Therefore, inhibitors of ALK5 would be beneficial in preventing peritoneal and sub-dermal fibrotic adhesions following surgical procedures.
Surprisingly, it has now been discovered that a class of 2-pyridyl substituted triarylimidazoles of formula (I), function as potent and selective non-peptide inhibitors of ALK5 kinase and therefore, have utility in the treatment and prevention of various disease states mediated by ALK5 kinase mechanisms, such as chronic renal disease, acute renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcers, occular disorders, corneal wounds, diabetic nephropathy, impaired neurological function, Alzheimer""s disease, trophic conditions, atherosclerosis, peritoneal and sub-dermal adhesion, any disease wherein fibrosis is a major component, including, but not limited to lung fibrosis and liver fibrosis, and restenosis.
According to the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
wherein R1 is naphthyl, anthracenyl, or phenyl optionally substituted with one or more substituents selected from the group consisting of halo, C1-6alkoxy, C1-6alkylthio, C1-6alkyl, xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Ph, xe2x80x94Sxe2x80x94(CH2)nxe2x80x94Ph, cyano, phenyl, and CO2R, wherein R is hydrogen or C1-6alkyl and n is 0, 1, 2 or 3; or R1 is phenyl fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to two heteroatoms, independently selected from N, O and S;
R2 is H, NH(CH2)nxe2x80x94Ph or NHxe2x80x94C1-6alkyl, wherein n is 0, 1, 2 or 3;
R3 is CO2H, CONH2, CN, NO2, C1-6alkylthio, xe2x80x94SO2xe2x80x94C1-6alkyl, C1-6alkoxy, SONH2, CONHOH, NH2, CHO, CH2OH, CH2NH2, or CO2R, wherein R is hydrogen or C1-6alkyl; and
one of X1 and X2 is N or CRxe2x80x2, and the other is NRxe2x80x2 or CHRxe2x80x2 wherein Rxe2x80x2 is hydrogen, OH, C1-6alkyl, or C3-7cycloalkyl; or when one of X1 and X2 is N or CRxe2x80x2 then the other may be S or O.
As used herein, the double bond indicated by the dotted lines of formula (I), represent the possible tautomeric ring forms of the compounds falling within the scope of this invention. It will be understood that when one of X1 and X2 is carbon and the other is nitrogen, then the double bond could be either to the carbon or the nitrogen. When X1 and X2 are both carbon, then the double bond could be to either X1 or X2. When X1 and X2 are both nitrogen, then the double bond is to the unsubstituted nitrogen.
Preferably R1 is optionally substituted naphthyl or phenyl. More preferably R1 is phenyl optionally substituted with one or more substituents selected from the group consisting of halo, C1-6alkoxy, C1-6alkylthio, and phenyl; or R1 is phenyl fused with an aromatic or non-aromatic cyclic ring of 5-7 members wherein said cyclic ring optionally contains up to two heteroatoms, independently selected from N, O and S, for example R1 represents benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl, benzoxazolyl, benzothiazolyl, benzo[1,2,5]oxadiazolyl, benzo[1,2,5]thiadiazolyl or dihydrobenzofuranyl.
Preferably, R2 is positioned ortho to the nitrogen of the pyridyl ring. More preferably R2 is hydrogen.
Preferably R3 is CO2H, CONH2, CN, NO2, SONH2, CONHOH, NH2, CHO, CH2OH or CH2NH2.
Preferably one of X1 and X2 is N or CRxe2x80x2, and the other is NRxe2x80x2 or CHRxe2x80x2 wherein Rxe2x80x2 is hydrogen, C1-6alkyl, or C3-7cycloalkyl, provided that at least one of X1 and X2 is N or NRxe2x80x2; or one of X1 and X2 is N and the other is O. More preferably one of X1 and X2 is N and the other is NRxe2x80x2.
Preferably each Rxe2x80x2 is hydrogen.
Specific compounds of the invention which may be mentioned include the following and pharmaceutically acceptable salts thereof:
4-[4-(4-Fluorophenyl)-5-(2-pyridyl)-1-hydroxy-1H-imidazol-2-yl]benzonitrile;
4-[4-(4-Fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzonitrile;
4-[4-(4-Fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzoic acid;
Methyl 4-[4-(4-fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzoate;
Ethyl 4-[4-(4-fluorophenyl)-5-(2-pyridyl)-1H-imidazol-2-yl]benzoate
4-(4-Benzo[1,3]dioxol-5-yl-1-hydroxy-5-pyridin-2-yl-1H-imidazol-2-yl)benzonitrile
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzonitrile;
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoic acid;
2-[4-Benzo[1,3]dioxol-5-yl-2-(4-nitrophenyl)-1H-imidazol-5-yl]pyridine;
3-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)phenylamine;
4-[4-(4-Fluorophenyl)-2-(4-nitrophenyl)-1H-imidazol-5-yl]pyridine;
4-[4-(4-Fluorophenyl)-5-pyridin-2-yl-1H-imidazol-2-yl)phenylamine
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)phenyl]methanol;
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzamide;
4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]-benzonitrile;
4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;
4-[4-(2,3-Dihydro-benzofuran-5-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;
3-[4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzonitrile;
4-[4-(2,3-Dihydro-benzofuran-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzonitrile;
4-[4-(2,3-Dihydro-benzofuran-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;
3-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoic acid;
4-[4-(4-Methoxyphenyl)-5-(2-pyridyl)-1H-imidazol-2yl]benzonitrile;
4-[4-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;
4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1-methyl-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide;
4-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-1-methyl-4-pyridin-2-yl-1H-imidazol-2-yl]benzamide;
4-(5-Benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-oxazol-2-yl)benzonitrile;
4-(5-Benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-oxazol-2-yl)benzamide; and
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-pyrrol-2-yl)benzamide.
Suitable, pharmaceutically acceptable salts of the compounds of formula (I) include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate, or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate, and stearate.
Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
Certain of the compounds of formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such forms, in particular the pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably at least 10% of a compound of the formula (I) or pharmaceutically acceptable derivative thereof.
The term xe2x80x9cC1-6alkylxe2x80x9d as used herein whether on its own or as part of a larger group e.g. C1-6alkoxy, means a straight or branched chain radical of 1 to 6 carbon atoms, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.
C1-6 haloalkyl groups may contain one or more halo atoms, a particular C1-6 haloalkyl group that may be mentioned in CF3.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d are used interchangeably herein to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
The term xe2x80x9cC3-7cycloalkylxe2x80x9d as used herein means cyclic radicals of 3 to 7 carbons, including but not limited to cyclopropyl, cyclopentyl and cyclohexyl.
The term xe2x80x9carylxe2x80x9d as used herein means 5- to 14-membered substituted or unsubstituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems, including, but not limited to phenyl and naphthyl.
The term xe2x80x9cALK5 inhibitorxe2x80x9d as used herein means a compound, other than inhibitory smads, e.g. smad6 and smad7, which selectively inhibits the ALK5 receptor preferentially over p38 or type II receptors.
The term xe2x80x9cALK5 mediated disease statexe2x80x9d as used herein means any disease state which is mediated (or modulated) by ALK5, for example a disease which is modulated by the inhibition of the phosphorylation of smad 2/3 in the TGF-1xcex2 signaling pathway.
The term xe2x80x9culcersxe2x80x9d as used herein includes, but is not limited to, diabetic ulcers, chronic ulcers, gastric ulcers, and duodenal ulcers.
The compounds of formula (I) can be prepared by art-recognized procedures from known or commercially available starting materials. If the starting materials are unavailable from a commercial source, their synthesis is described herein, or they can be prepared by procedures known in the art.
Specifically, compounds of formula (I) wherein one of X1 and X2 is N and the other is NH or Nxe2x80x94OH may be prepared as illustrated in Scheme 1 for compounds wherein X1 is N and X2 is NH or Nxe2x80x94OH. Using the method detailed in U.S. Pat. No. 3,940,486, N-methoxy-N-methylaryl amide is alkylated with the anion generated from a 2(6)-methylpyridine to give a ketone. The ketone is treated with sodium nitrite to form the oxime which is condensed with an aldehyde and NH4OAc to give a hydroxy imidazole. The hydroxy imidazole may then be reduced with triphenylphosphite by the method described in U.S. Pat. No. 5,656,644 to give the corresponding imidazole. 
Alternatively, the ketone may be oxidised to a diketone with HBr in DMSO. This diketone can then be condensed with a suitably substituted benzaldeyde and ammonium acetate to give the imidazole according to the method outlined in WO 98/56788 and as illustrated in Scheme 2 for compounds wherein X1 is N and X2 is NH. 
Non-selective alkylation of the imidazole nitrogen (using one of the procedures outlined in N. J. Liverton et al; J. Med. Chem., 1999, 42, 2180-2190) with a compound of formula Lxe2x80x94Rxe2x80x2 wherein L is a leaving group, e.g. halo, sulfonate or triflate, will yield both isomers of the compounds where one of X1 or X2 is NRxe2x80x2 wherein Rxe2x80x2 is C1-6alkyl, or C3-7cycloalkyl, as illustrated in Scheme 3, the isomers can be separated by chromatographic methods. 
Compounds of formula (I) wherein one of X1 and X2 is N and the other is O may be prepared according to Scheme 4. The oximino ketone may be reduced via catalytic hydrogen to afford the amino ketone which can be further reacted with an appropriately substituted benzoyl chloride compound. Reaction of the amide product with thionyl chloride affords the oxazole product. 
Compounds of formula (I) where one of X1 and X2 is CH or CHRxe2x80x2 may be prepared according to Scheme 5. A suitably substituted acetophenone and a benzaldehyde are condensed under basic conditions to afford the enone aldol product. This enone is then reacted with a pyridine-2-carboxaldehyde under sodium cyanide catalysis to afford the 1,4-diketone which is condensed with ammonium acetate to afford the pyrrole. 
During the synthesis of the compounds of formula (I) labile functional groups in the intermediate compounds, e.g. hydroxy, carboxy and amino groups, may be protected. A comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in for example Protective Groups in Organic Chemistry, T. W. Greene and P. G. M. Wuts, (Wiley-Interscience, New York, 2nd edition, 1991).
Further details for the preparation of compounds of formula (I) are found in the examples.
The compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, and more preferably 10 to 100 compounds of formula (I). Libraries of compounds of formula (I) may be prepared by a combinatorial xe2x80x98split and mixxe2x80x99 approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds of formula (I) or pharmaceutically acceptable salts thereof.
The invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease mediated by the ALK5 receptor in mammals.
The invention further provides a method of treatment of a disease mediated by the ALK5 receptor in mammals, comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
ALK5-mediated disease states, include, but are not limited to, chronic renal disease, acute renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcers, ocular disorders, corneal wounds, diabetic nephropathy, impaired neurological function, Alzheimer""s disease, trophic conditions, atherosclerosis, any disease wherein fibrosis is a major component, including, but not limited to peritoneal and sub-dermal adhesion, lung fibrosis and liver fibrosis, and restenosis.
By the term xe2x80x9ctreatingxe2x80x9d is meant either prophylactic or therapeutic therapy.
The invention further provides a method of inhibiting the TGF-xcex2 signaling pathway in mammals, for example, inhibiting the phosphorylation of smad2 or smad3 by the type I or activin-like kinase ALK5 receptor, which method comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the TGF-xcex2 signaling pathway in mammals.
The invention further provides a method of inhibiting matrix formation in mammals, for example, by inhibiting the phosphorylation of smad2 or smad3 by the type I or activin-like kinase ALK5 receptor, which method comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting matrix formation in mammals.
The compounds of formula (I) and pharmaceutically acceptable salts thereof, may be administered in conventional dosage forms prepared by combining a compound of formula (I) with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
The pharmaceutical compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
The compositions may be formulated for administration by any route. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.
It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of formula (I) will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of the compound of formula (I) given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
No toxicological effects are indicated when a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the above-mentioned dosage range.
All publications, including, but not limited to, patents and patent applications cited in this specification, are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.